The ability of cells to adhere to one another plays a critical role in development, normal physiology, and disease processes. This ability is mediated by adhesion molecules, generally glycoproteins, expressed on the cell surface. Several important classes of adhesion molecules include the integrins, the selectins, and members of the immunoglobulin (Ig) superfamily. Selectins play a central role in mediating leukocyte adhesion to activated endothelium and platelets.
Blood clotting, along with inflammation and tissue repair, are host defense mechanisms which function in parallel to preserve the integrity of the vascular system after tissue injury. In response to tissue injury, platelets, endothelial cells and leukocytes are essential for the formation of a platelet plug, deposition of leukocytes in injured tissue, initiation of inflammation, and wound healing.
P-selectin, also known as CD62, granule membrane protein-140 (GMP-140), and platelet activation-dependent granule external membrane protein (PADGEM), is an integral membrane glycoprotein that is expressed on vascular endothelial cells and platelets, and is involved in the recognition of various circulating cells. The P-selectin molecule has an N-terminal lectin domain, a region with homology to epidermal growth factor, a region with homology to complement regulatory proteins, a transmembrane domain, and a short cytoplasmic tail. The P-selectin ligand includes the Lex carbohydrate structure, sialic acid, and the PSGL-1 protein (U.S. Pat. No. 5,843,707).
P-selectin is constitutively stored in secretory granules (e.g., α-granules and Weibel-Palade bodies) and is translocated to the surface of platelets and endothelial cells in response to a variety of stimuli, including cell activation, where it mediates platelet-leukocyte and endothelium-leukocyte interactions. The cell surface expression of P-selectin is tightly regulated, and P-selectin is rapidly shed from the cell surface upon platelet activation, appearing as a soluble fragment in the plasma (Berger, G. et al. Blood (1998)92:4446-4452). Soluble P-selectin may also result from an alternatively spliced isoform of P-selectin lacking the transmembrane domain (Ishiwata, N. et al. J Biol Chem (1994)269:23708). The plasma of healthy humans and mice contains little soluble P-selectin, as detected by ELISA, and an increase in plasma P-selectin concentration may indicate in vivo activation of and/or damage to platelets and endothelial cells.
In addition to its role in leukocyte rolling and extravasation in inflammation, P-selectin mediates platelet-leukocyte adhesion within thrombi, and increases tissue factor expression on monocytes, thereby promoting fibrin deposition by leukocytes and thrombogenesis (Palabrica, T. et al. Nature (1992)359:848-851; Celi, A. et al. Proc Natl Acad Sci USA (1994)91:8767-8771).